In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) form the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the group II can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are chronic and acute pain, Huntington""s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
The present invention is a compound of formula I 
wherein
R is selected from the group consisting of cyano,
fluoro-lower alkyl,
lower alkoxy,
fluoro-lower alkoxy,
unsubstituted pyrrol-1-yl, and pyrrol-1-yl substitued by one to three substituents selected from the group consisting of
fluoro, chloro, cyano, unsubstituted phenyl or phenyl substituted by halogen,
xe2x80x94(CH2)1-4-hydroxy, fluoro-lower alkyl, lower alkyl, xe2x80x94(CH2)n-lower alkoxy,
xe2x80x94(CH2)nxe2x80x94C(O)Oxe2x80x94Rxe2x80x3, xe2x80x94(CH2)1-4xe2x80x94NRxe2x80x2Rxe2x80x3, hydroxy-lower alkoxy and
xe2x80x94(CH2)nxe2x80x94CONRxe2x80x2Rxe2x80x3;
R2 is selected from the group consisting of
halogen,
hydroxy,
lower alkyl,
fluoro-lower alkyl,
lower alkoxy,
hydroxymethyl,
hydroxyethoxy,
lower alkoxy-(ethoxy)m, wherein m=1 to 4,
lower alkoxymethyl,
cyanomethoxy,
morpholine-4-yl,
thiomorpholine-4-yl,
1-oxothiomorpholine-4-yl,
1,1-dioxothiomorpholine-4-yl,
4-oxo-piperidine-1-yl
4-alkoxy-piperidine-1-yl,
4-hydroxy-piperidine-1-yl,
4-hydroxyethoxy-piperidine-1-yl,
4-lower alkyl-piperazine-1-yl,
alkoxycarbonyl,
2-dialkylamino-ethylsulfanyl,
N,N-bis lower alkylamino lower alkyl,
carbamoylmethyl,
alkylsulfonyl
lower alkoxycarbonyl-lower alkyl,
alkylcarboxy-lower alkyl,
carboxy-lower alkyl,
alkoxycarbonylmethylsulfanyl,
carboxymethylsulfanyl,
1,4-dioxa-8-aza-spiro[4.5]dec-8-yl,
carboxy-lower alkoxy,
cyano-lower alkyl,
2,3-dihydroxy-lower alkoxy,
carbamoylmethoxy,
2-oxo-[1,3]-dioxolan-4-yl-lower alkoxy,
N-(2-hydroxy-lower alkyl)-N-lower alkyl amino,
hydroxycarbamoyl-lower alkoxy,
2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5c]-pyrrol-5-yl,
lower alkoxy-carbamoyl-lower alkoxy,
3R-hydroxy-pyrrolidin-1-yl,
3,4-dihydroxy-pyrrolidin-1-yl,
2-oxo-oxazolidin-3-yl,
lower alkyl-carbamoylmethoxy,
aminocarbamoyl-lower alkoxy, and, when R1 is unsubstituted pyrrol-1-yl or pyrrol-1-yl substituted as described above, hydrogen;
Y is xe2x80x94CHxe2x95x90 or xe2x95x90Nxe2x80x94;
R3 is selected from the group consisting of halogen,
lower alkyl,
fluoro-lower alkyl,
lower alkoxy,
cyano,
xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94ORxe2x80x3,
(CH2)nxe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x3,
an unsubstituted five-membered aromatic heterocycle and a five-membered aromatic hetero cycle substituted by halogen fluoro-lower alkyl, fluoro-lower alkoxy, cyano, xe2x80x94(CH2)nxe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94ORxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94SO2xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94(CH2)nxe2x80x94C(NH2)xe2x95x90NRxe2x80x3, hydroxy, lower alkoxy, lower alkylthio, unsubstituted lower alkyl, or lower alkyl substituted by fluoro, hydroxy, lower alkoxy, cyano or carbamoyloxy;
Rxe2x80x2 is selected from the group consisting of hydrogen,
lower alkyl,
C3-C6-cycloalkyl,
fluoro-lower alkyl and
2-lower alkoxy lower alkyl;
Rxe2x80x3 is selected from the group consisting of hydrogen,
lower alkyl,
C3-C6-cycloalkyl,
fluoro-lower alkyl,
2-lower alkoxy lower alkyl,
xe2x80x94(CH2)2-4-di-lower alkylamino,
xe2x80x94(CH2)2-4-morpholinyl,
xe2x80x94(CH2)2-4-pyrrolidinyl,
xe2x80x94(CH2)2-4-piperidinyl or
3-hydroxy-lower alkyl;
n is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable addition salt thereof.
It has surprisingly been found that the compounds of formula I are metabotropic glutamate receptor antagonists. Compounds of formula I are distinguished by valuable therapeutic properties.
The compounds of formula I can also be used in form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, glyceride conjugates and the like. The prodrugs may add to the value of the present compounds advantages in absorption, pharmacokinetics in distribution and transport to the brain.
As compounds of the present invention are metabotropic glutamate receptor agonists, they can be used to treat or prevent acute and/or chronic neurological disorders responsive to a metabotropic glutamate receptor agonist in a method of treatment comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
All tautomeric forms of the compounds of the invention are within the scope of the invention.
A preferred compound of the invention of formula I is the compound, wherein R1 is trifluoromethyl. An exemplary preferred compound, wherein R2 is morpholine, is selected from the group consisting of
4-(8-morpholin-4-yl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile,
4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-7-morpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-7-morpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(3-hydroxymethyl-isoxazol-5-yl)-phenyl]-7-morpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
4-[3-(5-hydroxymethyl-isoxazol-3-yl)-phenyl]-7-morpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.
Also preferred is a compound of formula I, wherein R1 is trifluoromethyl and R2 is thiomorpholine selected from the group consisting of
4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-7-thiomorpholin-4-yl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
4-(4-oxo-8-thiomorpholin-4-yl-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile.
A further preferred compound of formula I wherein R1 is trifluoromethyl and R2 is lower alkoxy is selected from the group consisting of
7-methoxy-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-methoxy-4-[3-(5-pyrrolidin-1-ylmethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-(8-ethoxy-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile,
4-[3-(5-cyclopropylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-ethoxy-4-(3-{5-[(2,2,2-trifluoro-ethylamino)-methyl]-[1,2,3]triazol-1-yl}-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-ethoxy-4-(3-[1,2,3]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
7-methoxy-4-(3-[1,2,3]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.
Another preferred compound of formula I, wherein R1 is trifluoromethyl and R2 is lower alkyl or halogen is selected from the group consisting of
4-(8-methyl-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile,
7-chloro-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-chloro-4-[3-(5-cyclopropylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(5-cyclopropylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-methyl-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-chloro-4-(3-[1,2,4]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-chloro-4-(3-imidazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-chloro-4-(3-[1,2,3]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-methyl-4-(3-[1,2,4]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-(3-imidazol-1-yl-phenyl)-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
7-methyl-4-(3-[1,2,3]triazol-1-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(2-hydroxymethyl-5-methyl-thiazol-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.
A further preferred compound of formula I, wherein R1 is unsubstituted pyrrol-1-yl and wherein R2 is hydrogen, halogen, lower alkoxy-ethoxy or lower alkoxy, is selected from the group consisting of
4-(3-iodo-phenyl)-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-(3-imidazol-1-yl-phenyl)-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
8-pyrrol-1-yl-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
4-(3-oxazol-2-yl-phenyl)-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,
5-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-oxazole-4-carboxylic acid ethyl ester,
4-[3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one, and
4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.
Further preferred is a compound of formula I, wherein R1 is substituted pyrrol-1-yl and wherein R2 is hydrogen or lower alkoxy selected from the group consisting of
4-(2-chloro-phenyl)-1-[2-(3-cyano-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-yl]-1H-pyrrole-3-carbonitrile,
3-[4-oxo-7-(3-phenyl-pyrrol-1-yl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile, and
3-[7-(2-tert.-butyl-pyrrol-1-yl)-8-methoxy-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile.
Further preferred is a compound of formula 1, wherein R1 is cyano.
Yet another preferred compound of formula 1, is wherein R2 is morpholine or thiomorpholine. Preferred compounds of formula I in the scope of the present invention are further those, wherein R3 is cyano, an unsubstsituted five-membered aromatic heterocycle or a five-membered aromatic heterocycle substituted by xe2x80x94CH2OH.
The term xe2x80x9clower alkylxe2x80x9d used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a lower alkyl residue in the sense of the foregoing definition bound via an oxygen atom. Examples of xe2x80x9clower alkoxyxe2x80x9d residues include methoxy, ethoxy, isopropoxy and the like.
The term xe2x80x9chalogenxe2x80x9d embraces fluorine, chlorine, bromine and iodine.
The term xe2x80x9cfluoro-lower alkylxe2x80x9d means a lower alkyl residue, wherein one or more hydrogen-atoms may be replaced by fluoro.
The term xe2x80x9cfluoro-lower alkoxyxe2x80x9d denotes a lower alkoxy residue in the sense of the definition herein before, wherein one or more hydrogen-atoms is replaced by fluoro.
xe2x80x9cLower alkoxy-(ethoxy)mxe2x80x9d (m is 1, 2, 3 or 4) denotes a lower alkoxy residue in the sense of the foregoing definition bound via 1 to 4 xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94 groups, for example 2-methoxy-ethoxy.
The term xe2x80x9cC3-C6-cycloalkylxe2x80x9d means a cycloalkyl group containing 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term xe2x80x9calkylthioxe2x80x9d denotes a lower alkyl residue in the sense of the foregoing definition bound via an sulfur atom, for example methylsulfanyl.
The expression xe2x80x9cfive-membered aromatic heterocyclexe2x80x9d embraces furane, thiophene, thiazole, pyrrole, imidazole, pyrazole, oxazole, isoxazole, triazole, oxadiazole, thiadiazole and tetrazole. Preferred aromatic heterocycles are 1,2,3-triazole, isoxazole, 1,3-oxazole, 1,3-thiazole, 1,3,4-oxadiazole or imidazole.
xe2x80x9cSubstitutedxe2x80x9d means that a group is substituted with at least one, preferably one or two substituents independently selected from the specified group. The term xe2x80x9cunsubstitutedxe2x80x9d in this document is consistent with the generally accepted usage of this term.
The term xe2x80x9cpharmaceutically acceptable addition saltxe2x80x9d refers to any salt derived from a pharmaceutically acceptable inorganic or organic acid or base.
The compounds of formula I or a pharmaceutically acceptable salt thereof can be manufactured according to methods, which process comprises reacting a compound of formula II 
with a compound of formula IV or IVa 
wherein R is lower alkyl, prefereably ethyl or tert.-butyl, thereby forming a compound of formula III 
Deprotecting the amino group of the compound of formula III and cyclizing, forming a compound of formula I 
wherein R1, R2, R3 and Y are as described above, or reacting a compound of formula VI 
with a compound of formula IV 
forming a compound of formula V 
reducing the nitro group and cyclizing, thereby forming a compound of formula I 
wherein R1, R2, R3 and Y are as described above and, if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt. 
According to scheme A, compounds of formula I, in which Y, R1, R2 and R3 are as described above, can be prepared from compounds of formula II via an acylation-deprotection-cyclization sequence:
For example reacting compounds of formula II with a dioxinone IV, in which Y and R3 are as described above, in an inert solvent such as toluene or xylene at elevated temperatures, preferably between 80xc2x0 C. and 160xc2x0 C. gives rise to compounds of formula III.
Alternatively, compounds of formula III can also be prepared by for example reaction of a compound of formula II with a xcex2-ketoester (formula IVa), in which Y and R3 are as described above using the same conditions as described for the reaction with the dioxinones.
Afterwards, cleaving the BOC protecting group in compounds of formula III and concomitant cyclization of the deprotected compound yields the desired compounds of formula I. Any other suitable amino protecting group, such as e.g. Fmoc or benzyloxycarbonyl (Z), can be alternatively used instead of the BOC group.
The deprotection-cyclization step can be carried out by treating the compounds of formula III with for example a Bronsted acid such as trifluoroacetic acid (TFA) in an inert solvent such as dichloromethane (DCM). The reaction is preferably carried out at temperatures between 0xc2x0 C. and 50xc2x0 C. It may be advantageous to use also anisole or 1,3-dimethoxybenzene as a carbocation scavenger in the reaction mixture. 
In addition, compounds of formula I, in which Y, R1, R2 and R3 are as described above, can be prepared according to scheme B, by for example reducing the nitro group in compounds of formula V to the amino group and subsequent heating of the reaction mixture to achieve the cyclization. The reduction can for example be carried out using hydrogen gas in presence of a suitable catalyst like for example Raney-Nickel. Other possible reduction methods are using tin(II)chloride (SnCl2.2H2O) in ethanol at temperatures between 70xc2x0 C. and 80xc2x0 C., iron-powder and acetic acid in mixtures of THF, water and ethanol at temperatures between 50xc2x0 C. and 80xc2x0 C., and also zinc-powder in the presence of ammonium chloride at temperatures between 20xc2x0 C. and 80xc2x0 C. The exact conditions for the respective compounds of formula I can be found in the experimental part.
Compounds of formula V, in which Y, R1, R2 and R3 are as described above, can be prepared according to scheme B by for example reacting a compound of formula VI, with a dioxinone (formula IV) in an inert solvent like for example toluene or xylene at elevated temperatures, preferably between 80xc2x0 C. and 160xc2x0 C. 
Compounds of formula II, in which R1 and R2 are as described above, can be prepared according to scheme C by reducing the nitro group in compounds of formula VII, in which R1 and R2 are as described above, to the amino group. The reduction can for example be carried out using hydrogen gas in presence of a suitable catalyst like for example Raney-Nickel or Palladium on carbon. Another possible reduction method is using tin(II)chloride (SnCl2.2H2O) in ethanol at temperatures between 70xc2x0 C. and 80xc2x0 C. (as described in Tetrahedron Lett. 1984, 25, 839), or alternatively in polar aprotic solvents, like DMF, DMA or NMP and the like, optionally in the presence of bases, like for example pyridine or triethylamine and the like, at temperatures between 0xc2x0 C. and 80xc2x0 C. Another suitable method is using zinc-powder in the presence of ammonium chloride in protic solvents like for example water or ethanol at temperatures between 20xc2x0 C. and 80xc2x0 C. The exact conditions for the respective compounds of formula II can be found in the experimental part.
Compounds of formula VII, in which R1 and R2 are as described above, can be prepared by different routes depending on the individual residues R1 and R2. 
As described in scheme D, compounds of the formula VIIa, in which R1 is as described above, R is chloro or fluoro and Rxe2x80x2 is hydrogen, can be prepared by protection of the amino group of compounds of the formula VIa, in which R1 is as described above, R is chloro or fluoro and Rxe2x80x2 is hydrogen, with a tert.-butoxycarbonyl-group (BOC). One possibility for the protection of the amino function is for example reacting compounds of formula VIa with di-tert.-butyl-carbonate in the presence of a base such as cesium carbonate. The reaction can be carried out in polar solvents such as acetone or butanone and the like at temperatures between 20xc2x0 C. and 80xc2x0 C.
Alternatively, the protection of the amino group can be achieved by preparing the intermediate isocyanate by treatment of compounds of the formula VIa, in which R1 is as described above, R is chloro or fluoro and Rxe2x80x2 is hydrogen, with diphosgene, preferably in aprotic solvents such as EtOAc or 1,4-dioxane at temperatures from 0xc2x0 C. to 100xc2x0 C., and subsequent treatment of the isocyanate with tert.-butanol in solvents such as dichloromethane or 1,2-dichloroethane and the like at temperatures between 20xc2x0 C. and 85xc2x0 C. to give the desired compounds of formula Va.
Another suitable method to achieve this protection step is the intermediate formation of a di-BOC compound by treatment of compounds of the formula VIa, in which R1 is as described above, R is chloro or fluoro and Rxe2x80x2 is hydrogen, with di-tert.-butyl-carbonate in the presence of DMAP in an aprotic solvent such as tetrahydrofuran and the like, followed by selective removal of a single BOC-group by treatment with a Bronsted-acid, like e.g. TFA, in aprotic solvents such as dichloromethane, chloroform or 1,2-dichloroethane at temperatures between 0xc2x0 C. and 20xc2x0 C. to give the desired compounds of formula Va.
Yet another suitable method to produce compounds of formula IXa is the intermediate formation of a Nxe2x80x94Ac-BOC compound by treatment of compounds of the formula VIa, in which R1 is as described above, R is chloro or fluoro and Rxe2x80x2 is acetyl, with di-tert.-butyl-carbonate in the presence of DMAP in an aprotic solvent such as tetrahydrofuran and the like, followed by selective removal of a single BOC-group by treatment with a Bronsted-base, like e.g. aqueous ammonia (NH4OH), in aprotic solvents such as tetrahydrofuran, diethylether or 1,4-dioxane and the like, at temperatures between 0xc2x0 C. and 20xc2x0 C. to give the desired compounds of formula Va.
Apparently, the protection of the amino function as shown in scheme D can be applied to a number of commercially available starting materials or compounds synthesized by standard transformations [e.g. nitration followed by selective ammonolysis of the halide in ortho-position to the newly introduced nitro-group as described in J. Med. Chem. 1994, 37,467; or ortho-nitration of acetanilide-compounds followed by deacetylation with for example aqueous potassium hydroxide solution or aqueous hydrochloric acid as described in Org. Synth. 1945, 25, 78 or in J. Med. Chem. 1985, 28, 1387] known to anyone skilled in the art to produce the corresponding 2-nitroanilines with the formula VIa, in which R1 is as described above, R is chloro or fluoro and Rxe2x80x2 is hydrogen, or 2-nitroacetanilides with the formula IXa, in which R1 is as described above, R is chloro or fluoro and Rxe2x80x2 is acetyl. The exact conditions for the respective compounds used in this invention can be found in the experimental part.
According to scheme E, compounds of formula VIb, in which R1 is pyrrol-1-yl optionally substituted as described above, and R is hydrogen or chloro, can be prepared from commercially available 2-nitro-1,4-phenylenediamine [CAS-No. 5307-14-2] [for R=H] or known 5-chloro-2-nitro-1,4-phenylenediamine [CAS-No. 26196-45-2] [for R=Cl] by selective condensation of the 4-amino-group with a suitable substituted 2,5-dimethoxytetrahydrofuran with the formula X, as described in J. Heterocycl. Chem. 1988, 25, 1003. 
The reaction is preferably carried out in acidic media, like for example acetic acid or propionic acid and the like, at temperatures between 40xc2x0 C. to 120xc2x0 C. The exact conditions for the respective compounds can be found in the experimental part.
Also according to scheme E, compounds of the formula VIc, in which R1 is pyrrol-1-yl and optionally substituted as described above and R2 is also as described above, can be prepared from N-(5-amino-2-nitro-phenyl)-acetamide-compounds of the formula IXb, in which R2 is as described above, by performing the same condensation reaction of the 5-amino-group with a suitable substituted 2,5-dimethoxytetrahydrofuran with the formula X as described for the reaction with the 2-nitro-1,4-phenylenediamine. The deacetylation of the compounds of formula IXc, in which R1 is pyrrol-1-yl and optionally substituted as described above and R2 is also as described above, to produce compounds of the formula VIc, in which R1 is pyrrol-1-yl and optionally substituted as described above and R2 is also as described above, can be done by standard acidic or basic hydrolysis reaction known to someone skilled in the art and the exact conditions for the respective compounds used in this invention can be found in the experimental part.
The synthesis of the corresponding N-(5-amino-2-nitro-phenyl)-acetamides with the formula IXb, in which R2 is as described above, follows standard procedures known to someone skilled in the art and the exact conditions for the respective compounds used in this invention can be found in the experimental part.
The corresponding substituted 2,5-dimethoxytetrahydrofurans with the formula X, in which Ra, Rb and Rc are as described above in the general claim for the pyrrol-1-yl compounds, are either commercially available, or synthesized from the suitable substituted furan, as shown in scheme F. The corresponding substituents can optionally be protected with suitable protecting groups, known to someone skilled in the art, or alternatively can be introduced after the pyrrol ring synthesis. The two-step sequence consists of reacting the furan with bromine in MeOH at low temperature, like for example xe2x88x9235xc2x0 C., followed by treatment with base, like for example triethyl-amine and the like or potassium carbonate or sodium hydrogen carbonate and the like. The resulting 2,5-dimethoxydihydrofuran with the formula VIII, in which Ra, Rb and Rc are as described above, can be reduced by catalytic hydrogenation, preferably in MeOH with catalysts like for example Palladium on carbon or Raney-Nickel and the like, to produce the desired 2,5-dimethoxytetrahydrofurans with the formula X. An example for this sequence can be found in Tetrahedron 1971, 27, 1973-1996. 
The exact conditions for the individual compounds to be synthesized can be found in the experimental part. 
Another method of preparing compounds with the formula VIc, in which R1 is pyrrol-1-yl, optionally substituted as described above, is by nucleophilic substitution reaction of compounds of the formula VId, in which R is chloro or fluoro and R2 is as described above, with the corresponding pyrrol as shown in scheme F. The reaction is preferably carried out in a polar, aprotic solvent such as dimethyl formamide, N-methyl-pyrrolidone or dimethyl sulfoxide and the like. The base can be selected from the sterically hindered amines such as triethylamine or Hxc3xcinig""s base, alkoxides such as sodium methoxide and tert.-butoxide, or hydrides such as sodium hydride. The reaction can be performed at temperatures between 20xc2x0 C. and 110xc2x0 C., depending on the individual compounds to be synthesized. The exact conditions for the respective compounds used in this invention can be found in the experimental part.
As shown in scheme H, compounds of formula VIb and VIIc, in which R2is attached via a sulfur- or nitrogen-atom, respectively, and substituted with Rxe2x80x2 and Rxe2x80x3 as described above, can be prepared from compounds with the formula VIIa, in which R1 is as described as above and R is chloro or fluoro, by a nucleophilic substitution reaction with the respective amines or mercaptanes in the presence of a suitable base. 
The reaction is preferably carried out in a polar, aprotic solvent such as dimethyl formamide, N-methyl-pyrrolidone or dimethyl sulfoxide and the like. The base can be selected from the sterically hindered amines such as triethylamine or Hxc3xcinig""s base, alkoxides such as sodium methoxide and tert.-butoxide, or hydrides such as sodium hydride. The reaction can be performed at temperatures between 20xc2x0 C. and 110xc2x0 C., depending on the individual compounds to be synthesized.
As shown in scheme I, compounds of formula VId, in which R2 is attached via an oxygen atom and Rxe2x80x2 is as described as above, can be prepared from compounds of the formula VIa, in which R1 is as described above and R is chloro or fluoro, by a nucleophilic aromatic substitution reaction with the respective alcohol (Rxe2x80x2OH) in the presence of a suitable base to produce compounds of the formula VIe, where the protection of the amino function can be performed as described earlier. The base can be selected from the class of Bronsted bases such as potassium hydroxide and the like. The reaction is preferably carried out in a polar, aprotic solvent such as dimethyl formamide, N-methyl-pyrrolidone or dimethyl sulfoxide and the like at temperatures between 20xc2x0 C. and 100xc2x0 C. 
Yet another method of preparing compounds of the formula VIId is using O-allyl compounds with the formula VIIe, in which R1 is as described above, and perfoming a deallylation-alkylation sequence as outlined in scheme I. The deallylation is preferably carried out by transition-metal catalyzed isomerisation, e.g. in the presence of Rhodium(I)-salts like for example Wilkinson""s catalyst [(PPh3)3RhCl] or Palladium(II)-salts such as [(PPh3)2PdCl2], followed by aqueous acid hydrolysis of the resulting vinyl ether. An example for this procedure can be found in J. Org. Chem. 1973, 38, 3224. Another method for the deallylation is the reaction with Palladium(0)-complexes such as [(PPh3)4Pd] in the presence of excess of a secondary amine, as for example morpholine, as described for example in Synthesis 1996, 755. The alkylation of the resulting phenols with the formula VIIf, in which R1 is as described above, to the desired compounds of the formula VIId can be carried out with electrophilic reagents of the formula Rxe2x80x94X, in which R has the meaning of lower alkyl, lower alkenyl, alkyl acetate or benzyl and X represents a leaving group, for example iodide, bromide, methanesulfonate or tolylsulfonate, in a suitable solvent in the presence of a base. The reaction is preferably carried out in polar, aprotic solvents, for example chlorinated solvents such as dichloromethane, chloroform or dichloroethane, or amides, for example dimethylformamide, dimethylacetamide and N-methyl-pyrrolidone, or sulfoxides, for example dimethyl sulfoxide. The base can be selected from the sterically hindered amines such as Hxc3xcinig""s base, alkoxides such as sodium methoxide and tert.-butoxide, hydrides such as sodium hydride, hydroxides such as potassium hydroxide, carbonates such as potassium carbonate or hydrogen carbonates such as potassium hydrogen carbonate. The reaction can be performed at temperatures between xe2x88x9220xc2x0 C. and 80xc2x0 C., depending on the individual compounds to be synthesized. For the synthesis of the O-tert.-butyl compounds with the formula VIId, in which R1 is as described above and R2 is tert.-butoxy, the phenols with the formula VIIf can be treated with DMF-di-tert.-butylacetal in toluene or benzene at 80xc2x0 C. as described in Synthesis 1983, 135. 
According to synthetic scheme J, compounds of formula VIIg, in which R2 is attached via a carbon atom and is as described above, can be prepared from compounds with the formula VIIa, in which R1 is as described as above and R is chloro or fluoro, by a nucleophilic substitution reaction with a malonic acid ester or -half-ester in the presence of a base as described for example in Org. Prep. Proc. Int. 1990, 22, 636-638, followed by the removal of one of the alkyl carboxylates via decarboxylation as described for example in Synthesis 1993, 51. The exact reaction conditions vary with the identity of the individual compounds and are described in the examples. 
According to Scheme K, the dioxinones and xcex2-keto esters building blocks with the formula IV and IVa can be prepared by methods known to someone skilled in the art from the corresponding carboxylic acid derivatives R3xe2x80x94COR, i.e. free acids, methyl or ethyl esters and acid chlorides. The exact conditions for the corresponding compounds can be found in the experimental part.
The pharmaceutically acceptable salts of the compound of formula I can be manufactured readily according to known methods and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I.
The compounds of formula I and or pharmaceutically acceptable salts thereof are metabotropic glutamate receptor antagonists. A method of treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits comprises administering an effective amount of the compound of formula I or a salt thereof to a person in need of such treatment. The method of the invention is useful for other indications such as restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further indications treatable by the method of the invention are acute and chronic pain, Huntington""s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The compounds of formula I or a pharmaceutically acceptable salt thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations in a suitable pharmceutical carrier. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I or a pharmaceutically acceptable salt thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such compositions which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
The present invention relates also to the use of compounds of formula I and of pharmaceutically acceptable salts thereof for in a method of treatment, especially for the control or prevention of acute and/or chronic neurological disorders of the aforementioned kind.
In Table I below some specific Ki values of preferred compounds of the invention are presented. These values were obtained by indirect measurement of the affinity of the compounds for the recombinant rat mGluR2 expressed in CHO cells using a displacement binding assay with 3H-LY354740.
Transfection and Cell Culture
cDNA encoding the rat mGlu2 receptor protein in pBluescript II was obtained from Prof. S. Nakanishi (Kyoto, Japan), and subcloned into the eukaryotic expression vector pcDNA I-amp from Invitrogen (NV Leek, The Netherlands). This vector construct (pcD1mGR2) was co-transfected with a psvNeo plasmid encoding the gene for neomycin resistance, into CHO cells by a modified calcium phosphate method described by Chen and Okayama (1988). The cells were maintained in Dulbecco""s Modified Eagle medium with reduced L-glutamine (2 mM final concentration) and 10% dialysed foetal calf serum from Gibco BRL (Basel, Switzerland). Selection was made in the presence of G-418 (1000 ug/mL final). Clones were identified by reverse transcription of 5 xcexcg total RNA, followed by PCR using mGlu2 receptor specific primers 5xe2x80x2-atcactgcttgggtttctggcactg-3xe2x80x2 and 5xe2x80x2-agcatcactgtgggtggcataggagc-3xe2x80x2 in 60 mM Tris HCl (pH 10), 15 mM (NH4)2SO4, 2 mM MgCl2, 25 units/mL Taq Polymerase with 30 cycles annealing at 60xc2x0 C. for 1 min., extention at 72xc2x0 C. for 30 s, and 1 min. 95xc2x0 C. denaturation.
Membrane Preparation
Cells, cultured as above, were harvested and washed three times with cold PBS and frozen at xe2x88x9280xc2x0 C. The pellet was resuspended in cold 20 mM HEPES-NaOH buffer containing 10 mM EDTA (pH 7.4), and homogenised with a polytron (Kinematica, AG, Littau, Switzerland) for 10 s at 10000 rpm. After centrifugation for 30 min. at 4xc2x0 C., the pellet was washed once with the same buffer, and once with cold 20 mM HEPES-NaOH buffer containing 0.1 mM EDTA, (pH 7.4). Protein content was measured using the Pierce method (Socochim, Lausanne, Switzerland) using bovine serum albumin as standard.
[3H]-LY354740 Binding
After thawing, the membranes were resuspended in cold 50 mM Tris-HCl buffer containing 2 mM MgCl2 and 2 mM CaCl2, (pH 7) (binding buffer). The final concentration of the membranes in the assays was 25 xcexcg protein/mL. Inhibition experiments were performed with membranes incubated with 10 nM [3H]-LY354740 at room temperature, for 1 hour, in presence of various concentrations of the compound to be tested. Following the incubations, membranes were filtered onto Whatmann GF/C glass fiber filters and washed 5 times with cold binding buffer. Non specific binding was measured in the presence of 10 xcexcM DCG IV. After transfer of the filters into plastic vials containing 10 mL of Ultima-gold scintillation fluid (Packard, Zxc3xcirich, Switzerland), the radioactivity was measured by liquid scintillation in a Tri-Carb 2500 TR counter (Packard, Zxc3xcirich, Switzerland).
Data Analysis.
The inhibition curves were fitted with a four parameter logistic equation giving IC50 values, and Hill coefficients and the Ki values were calculated using the Cheng and Prusoff equation (Cheng, Y. and Prusoff, W. H., Biochem. Pharmacol. 1973, 22, 3099-3108). A small Ki value expresses high affinity of the compound towards the receptor.